Overall objectives of the proposed study are to quantify carcinogenesis risks due to arsenic exposure at levels commonly found in the US. This research project shares the goals of the program of the program project of furthering our understanding of the environmental and health effects of arsenic has been identified as a potent skin carcinogen in highly exposed in rural regions of the northeastern US. Arsenic has been identified as a potent skin carcinogen in highly exposed human populations, but it is uncertain whether these effects occur at low levels. We propose to extend our epidemiological case-control study of bladder and skin of bladder and skin cancers in a US population: (1) to further resolve the dose-response relationship between low to moderate levels of arsenic exposure and risk of bladder cancer, (2) to test the hypothesis that arsenic is related specifically to intraepidermal carcinomas (including Bowen's disease) and multiple concomitant basal cell carcinomas (BCC) of the skin, and (3) to identify subgroups of individuals who may be at high risk of arsenic-associated cancers due to co-carcinogen exposure (e.g., low selenium). We will expand our investigations of individual biomarkers of arsenic exposure by testing the reliability of existing measures (drinking water, urine, and toenails) and exploring new molecular-genetic markers (i.e., based on cDNA arrays). New Hampshire is ideally suited to study the effects of low-dose arsenic exposure since it is one of the few regions of the country with a population-based surveillance system for non- melanoma skin cancer and over 20% of the private wells in the region contain levels of arsenic suspected of being carcinogenic. New Hampshire has unusually high bladder cancer mortality rates which are as yet unexplained, and there is accumulating evidence that these malignancies may result from arsenic ingestion. Thus, our study provides a unique opportunity to obtain results directly applicable to the US population and to help identify those at greater risk for arsenic-induced malignancies.